Socio-economic differences among low-birthweight infants in Hungary. Results of the Cohort '18 -Growing Up in Hungary birth cohort study.

BACKGROUND: As Hungary had the fifth-highest rate of low-birthweight (LBW) in the EU27 in 2020, LBW still remains a public health problem for the country. OBJECTIVE: Our goal is to examine whether LBW in Hungary is determined by the mothers' educational attainment, adjusted for other maternal characteristics (SES, health behaviour and psychological status during pregnancy) among mothers who gave birth in 2018-2019 in Hungary. METHODS: Source of data is the first and second wave of the Cohort '18 -Growing Up in Hungary longitudinal birth cohort study (n = 8185). It is based on a nationwide representative sample of pregnant women who gave birth between March 2018 and April 2019. All data were self-reported by mothers. We examined the association between maternal educational attainment and the risk of giving birth to an LBW-child (<2500g) by using logistic regression analysis. The highest educational attainment of the mother is measured by a five-value categorical variable (ISCED 97: 0-1; 2; 3C; 3-4; 5-6). RESULTS: 5.9% of women had LBW children. This rate is 18.0% among the lowest educated women with ISCED 97: 0-1; and it is 3.6% among the highest educated women with ISCED 97: 5-6. The adjusted predicted probabilities of LBW for these two groups of women are 13.5%, and 3.4% respectively, adjusted for household income quantiles, Roma ethnic background, residence place, smoking, alcohol consumption, and depression during pregnancy; controlled for mother's height, age at birth, parity and child's sex. Compared to women with the lowest level of education, the risk of giving birth to an LBW child decreases by 34.6% for those with the second level of education, by 60.1% for those with the third level of education, by 72.5% for those with the fourth level of education and by 77.2% for those with the highest level of education. Smoking during pregnancy significantly increases the risk of giving birth to an LBW by 54.9%. Being depressed at 7th month of pregnancy decreased the risk of giving birth to an LBW child in our sample by 13.2%, however the relationship is not significant. CONCLUSION: Our analysis confirmed that maternal educational attainment has a significant impact on the risk of LBW net of by other maternal SES and health behaviour factors. Nevertheless, even after adjusting for these covariates, inequality in LBW by maternal educational attainment persists.

Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism-Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer.

The importance of the prevention and control of non-communicable diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer, is increasing as a requirement of the aging population in developed countries and the sustainability of healthcare. Similarly, the 2013-2030 action plan of the WHO for the prevention and control of non-communicable diseases seeks these achievements. Adequate lifestyle changes, alone or with the necessary treatments, could reduce the risk of mortality or the deterioration of quality of life. In our recent work, we summarized the role of two central factors, i.e., appropriate levels of vitamin D and SIRT1, which are connected to adequate lifestyles with beneficial effects on the prevention and control of non-communicable diseases. Both of these factors have received increased attention in relation to the COVID-19 pandemic as they both take part in regulation of the main metabolic processes, i.e., lipid/glucose/energy homeostasis, oxidative stress, redox balance, and cell fate, as well as in the healthy regulation of the immune system. Vitamin D and SIRT1 have direct and indirect influence of the regulation of transcription and epigenetic changes and are related to cytoplasmic signaling pathways such as PLC/DAG/IP3/PKC/MAPK, MEK/Erk, insulin/mTOR/cell growth, proliferation; leptin/PI3K-Akt-mTORC1, Akt/NFĸB/COX-2, NFĸB/TNFα, IL-6, IL-8, IL-1ß, and AMPK/PGC-1α/GLUT4, among others. Through their proper regulation, they maintain normal body weight, lipid profile, insulin secretion and sensitivity, balance between the pro- and anti-inflammatory processes under normal conditions and infections, maintain endothelial health; balance cell differentiation, proliferation, and fate; and balance the circadian rhythm of the cellular metabolism. The role of these two molecules is interconnected in the molecular network, and they regulate each other in several layers of the homeostasis of energy and the cellular metabolism. Both have a central role in the maintenance of healthy and balanced immune regulation and redox reactions; therefore, they could constitute promising targets either for prevention or as complementary therapies to achieve a better quality of life, at any age, for healthy people and patients under chronic conditions.

Educational Differences in Cohort Fertility Across Sub-national Regions in Europe.

Educational differences in female cohort fertility vary strongly across high-income countries and over time, but knowledge about how educational fertility differentials play out at the sub-national regional level is limited. Examining these sub-national regional patterns might improve our understanding of national patterns, as regionally varying contextual conditions may affect fertility. This study provides for the first time for a large number of European countries a comprehensive account of educational differences in the cohort fertility rate (CFR) at the sub-national regional level. We harmonise data from population registers, censuses, and large-sample surveys for 15 countries to measure women's completed fertility by educational level and region of residence at the end of the reproductive lifespan. In order to explore associations between educational differences in CFRs and levels of economic development, we link our data to regional GDP per capita. Empirical Bayesian estimation is used to reduce uncertainty in the regional fertility estimates. We document an overall negative gradient between the CFR and level of education, and notable regional variation in the gradient. The steepness of the gradient is inversely related to the economic development level. It is steepest in the least developed regions and close to zero in the most developed regions. This tendency is observed within countries as well as across all regions of all countries. Our findings underline the variability of educational gradients in women's fertility, suggest that higher levels of development may be associated with less negative gradients, and call for more in-depth sub-national-level fertility analyses by education.

Effect of cis- and trans-Monounsaturated Fatty Acids on Palmitate Toxicity and on Palmitate-induced Accumulation of Ceramides and Diglycerides.

Dietary trans fatty acids (TFAs) have been implicated in serious health risks, yet little is known about their cellular effects and metabolism. We aim to undertake an in vitro comparison of two representative TFAs (elaidate and vaccenate) to the best-characterized endogenous cis-unsaturated FA (oleate). The present study addresses the possible protective action of TFAs on palmitate-treated RINm5F insulinoma cells with special regards to apoptosis, endoplasmic reticulum stress and the underlying ceramide and diglyceride (DG) accumulation. Both TFAs significantly improved cell viability and reduced apoptosis in palmitate-treated cells. They mildly attenuated palmitate-induced XBP-1 mRNA cleavage and phosphorylation of eukaryotic initiation factor 2α (eIF2α) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), but they were markedly less potent than oleate. Accordingly, all the three unsaturated FAs markedly reduced cellular palmitate incorporation and prevented harmful ceramide and DG accumulation. However, more elaidate or vaccenate than oleate was inserted into ceramides and DGs. Our results revealed a protective effect of TFAs in short-term palmitate toxicity, yet they also provide important in vitro evidence and even a potential mechanism for unfavorable long-term health effects of TFAs compared to oleate.

Investigation of the putative rate-limiting role of electron transfer in fatty acid desaturation using transfected HEK293T cells.

Elevated fatty acid (FA) levels contribute to severe metabolic diseases. Unbalanced oversupply of saturated FAs is particularly damaging, which renders stearoyl-CoA desaturase (SCD1) activity an important factor of resistance. A SCD1-related oxidoreductase protects cells against palmitate toxicity, so we aimed to test whether desaturase activity is limited by SCD1 itself or by the associated electron supply. Unsaturated/saturated FA ratio was markedly elevated by SCD1 overexpression while it remained unaffected by the overexpression of SCD1-related electron transfer proteins in HEK293T cells. Electron supply was not rate-limiting either in palmitate-treated cells or in cells with enhanced SCD1 expression. Our findings indicate the rate-limiting role of SCD1 itself, and that FA desaturation cannot be facilitated by reinforcing the electron supply of the enzyme.

Microsomal pre-receptor cortisol production is inhibited by resveratrol and epigallocatechin gallate through different mechanisms.

Local activation of cortisol in hormone target tissues is a major determinant of glucocorticoid effect. Disorders in this peripheral cortisol metabolism play an important role in the development of metabolic diseases, such as obesity or type 2 diabetes mellitus. Hence, dietary factors influencing the activity of the involved enzymes can have major impacts on the risk of the above diseases. Resveratrol and epigallocatechin gallate (EGCG), two natural polyphenols found in several nutriments and in green tea, respectively, are well-known for their antiobesity and antidiabetic activities. EGCG has been shown to interfere with microsomal cortisol production through decreasing the luminal NADPH:NADP+ ratio. The aim of this study was to clarify if resveratrol also induces such a redox shift or causes any direct enzyme inhibition that influences local cortisol production. Cortisone-cortisol conversions and changes in NADPH levels were monitored in rat liver microsomal vesicles. Cortisol production was inhibited by resveratrol in a concentration dependent manner while the intrinsic reducing and oxidizing capacity as well as the NADPH level inside the ER-derived vesicles remained unaffected. Activity measurements performed in permeabilized microsomes confirmed that resveratrol, unlike EGCG, inhibits 11ß-hydroxysteroid dehydrogenase type 1 directly. Long-term moderation of pre-receptor cortisol production likely contributes to the beneficial health effects of both polyphenols. © 2018 BioFactors, 45(2):236-243, 2019.

Cellular toxicity of dietary trans fatty acids and its correlation with ceramide and diglyceride accumulation.

High fatty acid (FA) levels are deleterious to pancreatic ß-cells, largely due to the accumulation of biosynthetic lipid intermediates, such as ceramides and diglycerides, which induce ER stress and apoptosis. Toxicity of palmitate (16:0) and oleate (18:1 cis-Δ9) has been widely investigated, while very little data is available on the cell damages caused by elaidate (18:1 trans-Δ9) and vaccenate (18:1 trans-Δ11), although the potential health effects of these dietary trans fatty acids (TFAs) received great publicity. We compared the effects of these four FAs on cell viability, apoptosis, ER stress, JNK phosphorylation and autophagy as well as on ceramide and diglyceride contents in RINm5F insulinoma cells. Similarly to oleate and unlike palmitate, TFAs reduced cell viability only at higher concentration, and they had mild effects on ER stress, apoptosis and autophagy. Palmitate increased ceramide and diglyceride levels far more than any of the unsaturated fatty acids; however, incorporation of TFAs in ceramides and diglycerides was strikingly more pronounced than that of oleate. This indicates a correlation between the accumulation of lipid intermediates and the severity of cell damage. Our findings reveal important metabolic characteristics of TFAs that might underlie a long term toxicity and hence deserve further investigation.

Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes.

Activation of various interacting stress kinases, particularly the c-Jun N-terminal kinases (JNK), and a concomitant phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in ß-cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes.

Pediatric glioblastoma with giant cells and "supratentorial" primitive neuroectodermal component - case report and review of the literature.

INTRODUCTION: The glial differentiation in pediatric "supratentorial primitive neuroectodermal tumors" (sPNET) is occasionally revealed by immunohistochemistry with GFAP (glial fibrillary acidic protein) as isolated positive cells among undifferentiated cells, indicative of divergent cellular phenotypes. Large malignant glial tumors in sPNETs are extremely rare and challenge the neuropathologist by raising the possibility of glioblastomas with sPNET-like features (GB sPNET). The distinction between them is important because of their different treatment and prognostic. CASE PRESENTATION: A large parieto-occipital tumor with minimal ventricular invasion, in an 11-year-old girl, with a five-month clinical history, was proven to be a highly malignant biphasic tumor, consisting in a glioblastoma with giant cells, representing 75% of the tumor, and sPNET nodules, with one larger dominant nodule. The immunohistochemistry confirmed positivity for synaptophysin, neurofilament, neuron-specific enolase and CD56 in the sPNET compartment and for GFAP, CD56 and vimentin in the glioblastoma. In some parts of the tumor, the two components were well delineated from each other as in a "collision" tumor, but in others, the two different tumors were intermingled. It was histologically diagnosed as sPNET with double differentiation (glial and neural) or glioblastoma with sPNET-like features. CONCLUSIONS: These cases are very rare, few reported, especially in the pediatric population, and with high difficulties in histological differential diagnosis, subsequently reflected in the therapeutic decisions.

Targeting vascular endothelial growth factor receptor 2 and protein kinase D1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro.

Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways.

Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells.

Lipotoxicity refers to cellular dysfunctions caused by elevated free fatty acid levels playing a central role in the development and progression of obesity related diseases. Saturated fatty acids cause insulin resistance and reduce insulin production in the pancreatic islets, thereby generating a vicious cycle, which potentially culminates in type 2 diabetes. The underlying endoplasmic reticulum (ER) stress response can lead to even ß-cell death (lipoapoptosis). Since improvement of ß-cell viability is a promising anti-diabetic strategy, the protective effect of metformin, a known insulin sensitizer was studied in rat insulinoma cells. Assessment of palmitate-induced lipoapoptosis by fluorescent microscopy and by detection of caspase-3 showed a significant decrease in metformin treated cells. Attenuation of ß-cell lipotoxicity was also revealed by lower induction/activation of various ER stress markers, e.g. phosphorylation of eukaryotic initiation factor 2α (eIF2α), c-Jun N-terminal kinase (JNK), insulin receptor substrate-1 (IRS-1) and induction of CCAAT/enhancer binding protein homologous protein (CHOP). Our results indicate that the ß-cell protective activity of metformin in lipotoxicity can be at least partly attributed to suppression of ER stress.

Lipotoxicity in the liver.

Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21(st) century. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes, recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids, and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors, channels and transporters. However, it also induces endoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis. This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses.